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Alipov et al. Difference between native and desialylated LDL

Chemical composition of oxLDL is characterized by GLYCATED LDL
1.5 to 2 fold decreased levels of antioxidants, such
as coenzyme Q10, tocopherols, β-carotene, and Glycation of LDL occurs due to non-enzymatic reaction
lycopene, and increased content of oxidation products. of glucose and its metabolites with free amino groups
Intense oxidation of fatty acids, cholesterol and other of apoB-100 lysine. This process is highly intensive in
lipids leads to accumulation of 13-hydroperoxylinoleic patients with diabetes mellitus and metabolic syndrome
acid and other peroxides, hydroxides (e.g. because of the high glucose blood level. [66] In non-
13-hydroxylinoleic acid), prostaglandin derivatives diabetic patients, 4.8% of apoB-100 is glycated compared
(isoprostanes), various aldehydes (malondialdehyde, to 14.8% of total apoB glycated in patients with type II
oxovaleryl phosphatidylcholine, hexanal, etc.), diabetes. It was demonstrated that small-dense LDL is
lysophosphatidylcholine, 7-keto-cholesterol, various more susceptible to glycation in patients with metabolic
hydrocarbons, including pentane, and modified syndrome and type II diabetes than nLDL. [67] Glycation
phosphatidyl ethanolamine/serine products. Products makes LDL more sensitive to oxidation. Formation
of protein oxidation include: protein carbonyls, non- of glycated LDL and other advanced glycation end
enzymatic proteolyzed fragments, arginine, cysteine, products (AGEs) increases atherogenic properties
modified cysteine, lysine, histidine, methionine, of LDL and enhances lipid uptake by cultured aortic
tyrosine, and tryptophan, protein cross-linking products smooth-muscle cells. High concentration of AGEs
due to tyrosine cross-links and bifunctional aldehydes, leads to activation of the RAGE receptor pathway,
lipid-protein adducts which can be classified as which results in enhanced expression and NF-κB-
ceroids (lipofuscins). Many of the above mentioned dependent release of pro-inflammatory molecules.
modifications, as well as conformational changes, might That, in turn, promotes vessel wall damage, endothelial
lead to increased antigenicity. [62] Lack of antioxidants dysfunction, monocyte and macrophage migration and
makes oxLDL susceptible to further oxidation and recruitment to the vascular intima followed by oxidative
apolipoprotein degradation. In the bloodstream, oxLDL stress, vascular wall remodeling and atherosclerotic
is characterized by high density and increased negative lesion progression. [68] However, recent studies on
charge. A controlled study of LDL structural changes diabetic patients showed that glycated LDL level was
due to in vitro oxidation with copper ions showed similar not an independent risk factor for CVD. At the same
results. Small-angle X-ray scattering and dynamic time, patients with type I and II diabetes had a high level
light scattering techniques revealed high density, of small dense desialylated LDL particles with oxidative
electrical charge, and increased degree of flexibility modifications. [54] Therefore, glycation makes nLDL
of the apoB-100. [63] However, oxidation should not more susceptible to oxidation and enzymatic changes
be considered as the key modification leading to LDL and may be the first step atherogenic modification of
electronegativity because the concentration of oxLDL LDL in diabetic patients.
in normolipidemic plasma is orders of magnitude lower
than LDL(-) concentration. [17] DESIALYLATION IMPACT ON
ATHEROSCLEROSIS DEVELOPMENT
ELECTRONEGATIVE LDL
Under normal conditions, LDL lipid intake is controlled
LDL(-) chemical composition is characterized by by lipoprotein receptors. Modification of LDL, such
decreased sialic acid and antioxidant content, as oxidation and desialylation, allows LDL particles
increased triglycerides, nonesterified fatty acids to escape this limitation and enter arterial cells via
(NEFA), lysophosphatidylcholine, and ceramide levels different pathways. Sialic acid provides LDL with
compared to nLDL. [63,64] LDL(-) is also distinguished by negative charge, which protects the particle from
phospholipolytic activities and abnormal apoB-100 binding to arterial proteoglycans. The increased ability
conformation. [65] In nLDL, apoB-100 has a pentameric of enzymatically desialylated LDL to interact with
structure with alternating alpha helixes and beta proteoglycans was confirmed by Millar et al. [45] However,
pleated sheets. In LDL(-), apoB-100 has less alpha small dense desialylated LDL are electronegative and
helixes and more beta sheets, as well as an altered can interact with macrophage lectin receptors, therefore
pattern of exposed lysine residues that are involved in mediating the lipid uptake. [68] Increased cholesterol
lipoprotein receptor binding interactions. Changes in accumulation may also result from macrophage
apoB-100 structure may be caused by oxidation and scavenger receptor-mediated uptake followed by foam
nitration. [65] These chemical changes and presence cell formation and macrophage cytokine release, which
of electronegative charge in desialylated LDL makes causes inflammation and monocyte migration in the
it possible to suggest that these two fractions are intima. [70-72] Inhibition of Acyl-coenzyme A: cholesterol
identical. [16] acyltransferase activity by desialylated LDL is also
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